NO (nitric oxide) is formed from the amino acid L-arginine by several forms of NO synthases, and plays a role in a number of physiological functions, including the relaxation of airway smooth muscle. NO formed in endothelial cells in response to chemical agonists and to physical stimuli plays a key role in regulation of vascular tone, platelet aggregation and adhesion, as well as modulating smooth muscle proliferation (Haj-Yehia et al. (2000) Drug. Development Res. 50:528-536). NO overproduction has also been associated with numerous disease states (WO 99/66918). NO levels have been shown to be increased in the asthmatic airways (Kaminsky et al. (1999) J. Allergy Clin. Immunol 104(4)I:747-754). The role of NO in the respiratory system has been studied (Tamaoki et al. (1995) Am. J. Physiol. 268(6)I:C1342-C1346). NO has also been used in the treatment of asthmatics, though such treatments demonstrated a great deal of inter- and intra-individual variability (WO 01/32202).
Publications disclosing nitric oxide donor compounds or compounds which promote the synthesis of nitric oxide include WO 98/42661, WO 99/37616, WO 00/31060, WO 97/34871, WO 00/35434, WO 99/62509, WO 97/25984, WO 00/67754, WO 9961018, WO 99/61430, WO 97/31654, WO 96/32946, WO 00/53191, U.S. Pat. Nos. 6,248,895 and 6,232,331 and Wolf et al. (1998) J. Neurosurg. 89:279-288. Publications disclosing nitric oxide scavenger compounds include WO 98/55453.
The endothelium, in addition to producing NO, also produces superoxide (SO) anion and other reactive oxygen species (ROS) under physiological conditions. Despite SO being a reducing agent that is itself incapable of initiating oxidative reactions, SO is considered the most important source of oxidative stress. Compounds for the removal of SO are described in the art, including WO 96/39409 and U.K. Pat. App. No. 2349385A.
Many disease states, including diabetes mellitus and various cardiovascular diseases, are associated with oxidative stress and endothelial dysfunction. Nitroglycerin (GTN) has been used for the treatment of various types of myocardial ischemia Because of its pathogenic nature (chronicity with acute exacerbation), prophylactic and acute treatments are necessary to prevent complications with potentially fatal outcomes (>25% death for acute MI). However, the phenomenon of tolerance to the anti-anginal effects of GTN and to all other existing organic nitrates is of a special clinical significance. In particular, early development of tolerance to the drug is by far the most serious drawback of nitrate therapy.
A number of respiratory disorders have been recognized. Many of which have overlapping and interacting etiologies. The majority of these disorders are characterized by acute pulmonary vasoconstriction or bronchoconstriction. Inflammation and edema are also often associated with respiratory disorders such as asthma, respiratory distress syndrome (child or adult), bronchitis, pneumonia and others.
Various compounds and treatments for respiratory disorders are disclosed in the art, for example, in U.S. Pat. Nos. 6,299,863, 6,124,319, 6,297,762, 6,254,882, 6,083,993, 5,824,669, 5,821,259, RE 37,116E, WO 97/34871, WO 01/32202, WO 99/40787, WO 95/30641 and Australian Patent No. 733202.
At the therapeutic level, β2-agonists are the first drugs that are used in the acute treatment of asthma (Roberts et al, Lung (1990) 168:Suppl. 105-110, and Rees, BMJ (1991) 302:1166-7). It is more controversial whether they should be used for chronic maintenance therapy (Haahtela et al., NEJM (1991) 325:388-92 and Burrows and Lebowitz, NEJM (1992) 326:560-1). Several effective β2-agonists are currently available. However, patients may respond better to one drug over another so it is reasonable to switch drugs if a patient is not responding (Thompson et al., Clin Pharm. 1985; 4:383-8). The inhaled route of administration is the preferred route and a metered dose inhaler is the preferred way of administering the drug by inhalation. Methods of making aerosol formulations of β-agonists are known in the art, as described for example in U.S. Pat. No. 6,238,647.
Most β2-agonists cause somewhat similar adverse effects. These adverse effects include but are not limited to cardiovascular effects such as palpitations, increased heart rate, and tachycardia; central nervous system symptoms such as nervousness, dizziness, headache and drowsiness; respiratory side effects such as dyspnea, wheezing, drying or irritation of the oropharynx, coughing, chest pain and chest discomfort; hand tremors, muscle tremors, and immediate hypersensitivity reactions such as urticaria, angioedema, rash and even bronchospasms. In addition, some β2-agonists can cause angina, vertigo, central stimulation and insomnia, airway hyperreactivity (hypersensitivity), nausea, diarrhea, dry mouth and vomiting (see also Boushey, “Basic & Clinical Pharmacology” 7th Ed., pp. 118-151 and 325-342, Katzung, Ed. 1998, Appleton & Lange, Stamford, Conn.). N-agonists may sometimes cause systemic adverse effects such as weakness, fatigue, flushed feeling, sweating, unusual taste, hoarseness, muscle cramps and backaches.
Furthermore, patients have a tendency to develop a tolerance to the bronchodilating effect of β-agonists. This is related to desensitization, which is one of the most clinically significant phenomena involving the β-adrenergic receptor. It has been observed that patients in prolonged β-agonist therapy have a tendency to increase the dosage their medication. This occurs because after prolonged administration, the β-receptor appears to become desensitized to the agonist, thus requiring larger doses of the compound to effect an equivalent physiological response. Often an increase in dosage leads to an increase in the kind, number or severity of adverse effects (see e.g. Paterson et al: American Review of Respiratory Disease (1979) 120:844-1187); Lancet (1990) 336:1411-1412; Spitzer et al. New England J. Med. (1992).
There is a need for improved drugs for the treatment of respiratory disorders such as asthma